1. Technical Field
The present invention relates generally to compositions including and methods utilizing antisense oligonucleotides, and more particularly to the use of an adenosine A.sub.1 receptor antisense oligonucleotide in the prevention/treatment of alcohol and/or marijuana induced psycho-motor impairments.
2. Background Art
Alcohol and marijuana (Cannabis sativa) are among the oldest and most widely used drugs in the world. The major psychoactive ingredient of the marijuana plant is delta.sup.9 -tetrahydrocannabinol (.DELTA..sup.9 -THC) (Razdan, 1986). One of the characteristic pharmacological effects produced by alcohol and .DELTA..sup.9 -THC is motor impairment (MI), such as ataxia and a decrease in spontaneous motor activity (Hollister, 1986; Dewey, 1986). The impairment of motor functions by cannabinoid is well correlated with the presence of high density cannabinoid binding sites in the cerebellum and the basal ganglia (Herkanham et al., 1990; Mailleux and Vanderhaeghen, 1992). It has been suggested that the cannabinoid-induced motor impairments are due to cerebellar mediation (Herkanham et al., 1990).
Motor impairment in humans is one of the well known adverse consequences of alcohol drinking and marijuana smoking. Thus, marijuana and alcohol appear to produce, in a dose-related manner, a detrimental effect on the ability to drive an automobile. The consequences of use of both psychoactive drugs can be adverse not only for the drinker and smoker, respectively, but also for the safety of passengers in the drinker and smoker's automobile as well as for other non-smoking and non-drinking drivers. A striking deterioration of aircraft handling by pilots was demonstrated even 24 hours after smoking marijuana. Complex processes, including perception, attention, and information processing, which are involved in driving and flying, are impaired by doses equivalent to one or two cigarettes; the MI lasts for 4 to 8 hours, far beyond the time that the user perceives the subjective effects of the drug. A significant percent of marijuana users failed roadside sobriety test even 90 minutes after its smoking (Hollister, 1986). It is also well known that a high percentage of accident victims have ethanol in their blood. Furthermore, marijuana and alcohol are commonly used together. Ataxia and MI are the most conspicuous physical manifestation of alcohol consumption in animals and humans (Wallgren and Barry, 1970; Ritche, 1980). The MI produced by alcohol is additive to that induced by marijuana, resulting in rapid deterioration of driving performance (Dimijian, 1978; Reeve et al., 1985). These findings bear serious implications for driving, flying, operating rail/ship or performance of other complex tasks, even as long as a day after smoking marijuana and/or drinking alcohol. .DELTA..sup.9 -THC and other cannabinoids produce variety of pharmacological effects which appear to be mediated by the recently characterized cannabinoid receptors (Herkanham et al., 1990) in both humans and laboratory animals. Some of these pharmacological properties are unique to .DELTA..sup.9 -THC and psychoactive cannabinoids such as static ataxia in dogs and discriminative stimulus properties. The cannabinoids also possess many other properties such as analgesic, antiemetic, anticonvulsant and hypothermic which are shared by other drug groups. The recent identification and cloning of a specific cannabinoid receptor suggests that cannabinoids mimic endogenous compounds affecting neural signals for mood, memory, movement and pain. Cannabinoids have been reported to inhibit N-type calcium channels in neuroblastoma-glioma cells involving pertussis toxin-sensitive GTP-binding protein between cannabinoid receptors and calcium channels (Mackie and Hille, 1992). Some of the psychoactive effects of cannabinoids could be due to a calcium channel inhibition-induced decrease in excitability and neurotransmitter release (Mackie and Hille, 1992).
The pharmacological effects of adenosine (Dunwiddie and Worth, 1982; Crawley et al., 1981) bear similarity with some of the CNS effects of ethanol as well as .DELTA..sup.9 -THC such as causing MI and being, anticonvulsant, hypothermic and anticiceptive. The modulation of MI due to alcohol by brain adenosine has been first reported by us (Dar et al., 1983) and later confirmed and extended by other investigators (Proctor and Dunwiddie, 1984) as well as by us (Clark and Dar, 1988, 1989a, b, c; 1991; Dar, 1986, 1988, 1989, 1990a, b; 1992; 1995, 1996, 1997; Dar et al., 1993, 1994; Meng and Dar, 1994, 1995, 1996; Anwer and Dar, 1995a, b). Results from these studies have shown that adenosine agonists and antagonists when administered systemically (Dar et al., 1983; Clark and Dar, 1988) or icv (Dar, 1989, 1990a, 1992), significantly accentuate and attenuate, respectively, acute ethanol-induced MI and inhibition of spontaneous motor activity (SMA) mainly via A.sub.1 and less likely through A.sub.2 subtype of adenosine receptors (Clark and Dar, 1988; Dar, 1990a). Overall, these data suggest a possible functional relationship between ethanol-induced MI and A.sub.1 binding sites (Clark and Dar, 1988; Dar, 1990a). In addition, co-localization of adenosine A.sub.1 and cannabinoid receptors on the axons and axonal terminals of the glutamatergic granule cells in the cerebellum has been demonstrated (Pacheco et al., 1993).
Although adenosine fulfills some of the classical criteria of a neurotransmitter, the impact of this is diminished by the realization that most tissues can release adenosine in response to metabolic demand. Adenosine may thus act as a "retaliatory" metabolite (Newby, 1984) because it inhibits cell function, reduces the release of excitatory neurotransmitters and induces local vasodilatation. Adenosine, however, has been considered to act as a neuromodulator (Williams, 1989), a homeostatic regulatory substance (Schmitt, 1984) and even a neurotransmitter (Phillis and Wu, 1981). Also, adenosine is well known to produce distinct phyiological and pharmacological actions (Phillis and Wu, 1981; Snyder, 1985; Dunwiddie, 1985; Ribeiro and Sebastiao, 1986). For example, adenosine and its analogs depress firing of central neurons (Phillis and Wu, 1981), inhibit release of various neurotransmitters in brain tissue and modulate ion channels (Dunwiddie, 1985). These important neuroactive actions of adenosine are mediated via well recognized, methyl xanthine-sensitive extracellular receptors probably by modulating second messenger systems such as adenylate cyclase (Phillis and Barraco, 1985), inositol phospholipid metabolism (Rubio et al., 1989), or calcium homeostasis in brain tissues via direct interaction with calcium channels (Ribeiro and Sebastiao, 1986). The behavioral effects of adenosine have generally been studied using stable analogs of adenosine (Proctor and Dunwiddie, 1984; Barraco, 1985; Phillis et al., 1986). Many of these behavioral effects can be mimicked by drugs which alter endogenous levels of brain adenosine such as adenosine deaminase inhibitors and adenosine uptake blockers (Phillis et al., 1986).